Method and composition for treatment of inflammatory bowel disease

ABSTRACT

A composition in unit dosage form for the inhibition, prevention or treatment of inflammatory bowel disease comprising an effective amount of a compound having the formula:  
                 
 
     and a pharmaceutically acceptable carrier therefor. Also disclosed is a method for the inhibition, prevention or treatment of inflammatory bowel disease comprising administering to a human or non-human mammal in need thereof an effective amount of a compound having the formula:

[0001] Research leading to the completion of the invention was supportedin part by Grant Nos. 3203522-12, RO1HL42817 and RO1DK49108 awarded bythe National Institutes of Health (NIH). The United States Governmenthas certain rights in and to the claimed invention.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to the treatment of inflammatorybowel diseases.

[0004] 2. Description of the Prior Art

[0005] Inflammatory bowel disorders or diseases (IBD) encompass aspectrum of overlapping clinical diseases that appear to lack a commonetiology. IBD, however, are characterized by chronic inflammation atvarious sites in the gastrointestinal (GI) tract. Illustrative IBD areregional enteritis (or Crohn's disease), idiopathic ulcerative colitis,idiopathic proctocolitis and infectious colitis. Most hypothesesregarding the pathogenesis of IBD concern the implication ofimmunologic, infectious and dietary factors.

[0006] IBD are characterized histopathologically by ulceration,pseudomembranes, radiologically visible lesions, edema and the build-upof inflammatory cells; symptoms involve diarrhea, abdominal pain, weightloss and hypoproteinemia. Descriptions in the literature includeNorthfield, Drugs, Vol. 14, pages 198-206 (1977); Blaker et al, Eur. J.Pediatr., Vol. 139, pages 162-164 (1982); Singleton, TheGastroenterology Annual, pages 268-310 (1983); Saco et al, J. Amer.Acad. Dermatol., Vol. 4, pages 619-629 (1981); Prantera et al, Ital. J.Gastroenterol., Vol. 13, pages 24-27 (1981); Sales et al, Arch. Int.Med., Vol. 143, pages 294-299 (1983); and Ament, Inflammatory BowelDiseases, Martinus Nijhoff Publ., Boston, Mass., pages 254-268 (1982).Less frequent, but also possible, are mucosal inflammation of othersections of the GI tract, such as duodenitis, jejunitis and proctitis.

[0007] The clinical manifestations of ulcerative colitis and Crohn'sdisease share the common feature of inflammation. In ulcerative colitis,the earliest lesion is an inflammatory infiltration with abscessformation at the base of the crypts of Lieberkühn. Coalescence of thesedistended and ruptured crypts tends to separate the overlying mucosafrom its blood supply, leading to ulceration. The inflammatoryinvolvement is diffuse and superficial, usually limited to the mucosaand submucosa.

[0008] The clinical picture includes cramping, lower abdominal pain orrectal bleeding, soon followed by frequent, loose discharges consistingmainly of blood, pus and mucus with scanty fecal particles. The rectumand ampulla are usually found to be spastic.

[0009] In Crohn's disease (also known as regional enteritis orulcerative ileitis), the most prominent feature of the disease is thegranular, reddish-purple, edematous thickening of the bowel wall. In theearly phase of the disease, the prominent irritability, spasm and edemagive the appearance of a rigid contour to the diseased segmentradiogenographically.

[0010] The histological picture consists of dilated and tortuous lymphvessels and granulomatous structures which are made up predominantly ofepithelioid cells, lymphocytes and, occasionally, giant cells. With thedevelopment of inflammation, these granulomas often lose theircircumscribed borders and merge with the surrounding tissue reaction.Obstruction is the predominant clinical feature. The stools, althoughloose, are rarely bloody.

[0011] Idiopathic ulcerative colitis (UC) is a recurrent acute andchronic ulcero-inflammatory disorder principally affecting the rectumand left colon, but sometimes the entire large bowel. See Kirsner et al,N. Engl. J. Med., Vol. 306, pages 775-837 (1982). UC encompasses aspectrum of diffuse, continuous, superficial inflammation of the colonwhich begins in the rectum and extends to a variable proximal level. SeeCecil Textbook of Medicine, 19th Edition, page 699, Wyngaarden et al,ed., (1992). Matters relating to the etiology (i.e., definitiveetiopathogenesis is not known), epidemiology, pathogenesis, pathology,symptoms, diagnosis (e.g., endoscopy and radiography) and complications(e.g., cancer, intestinal complications such as rectal bleeding andtoxic megacolon, and extraintestinal complications such as anemia andleukocytosis) are set forth in relatively complete detail in the CecilText-book of Medicine, supra.

[0012] The manner in which UC is treated can vary and, typically, themedical treatment depends upon the severity of the symptoms exhibited bythe patient. Corticosteroids (e.g., prednisone), antibiotics (e.g.,tetracycline, sulfatrimethoprim, metronidazole and cephalexin) andimmuno-suppressants (e.g., 6-mercaptopurine and azathioprine) often areused for treating UC. Anti-inflammatory agents (e.g., sulfasalazine andmesalamine) are effective to some degree in some patients for thetreatment of acute UC. Certain anti-inflammatory agents are availablecommercially as Asacol from Rolm Pharma GmbH, Dipentum from KabiPharmacia AB and Rowasa [5-aminosalicylic acid (5-ASA)] from SolvayPharmaceuticals. In more severe cases or when the anti-inflammatoryagents fail to relieve the symptoms of UC, surgical procedures are used.Typical surgical procedures include colectomy, proctocolectomy andileostomy. See Cecil Textbook of Medicine, supra. Other treatmentmethods for gastrointestinal disorders have been proposed in U.S. Pat.Nos. 5,110,795 (Hahn), 5,112,856 (Gaginella et al), 5,216,002 (Gidda etal), 5,238,931 (Yoshikawa et al), 5,292,771 (Backström et al), 5,312,818(Rubin et al), 5,324,738 (Dinan et al), 5,331,013 (Ahlman et al),5,340,801 (Ewing et al), 5,368,854 (Rennick), 5,391,555 (Marshall etal), 5,552,439 (Panetta), 5,569,680 (Wu), 5,599,795 (McCann et al),5,604,231 (Smith et al), 5,691,343 (Sandborn) and 5,693,645 (Sharpe etal).

[0013] 6-Mercaptopurine (6 MP) and its prodrug azathioprine (AZA) havebeen used in the treatment of IBD for over twenty-five years. Multiplecontrolled trials and a recent meta-analysis support the efficacy of 6MP and AZA in Crohn's disease. See Willoughby et al, Lancet, Vol. ii,page 944 (1971); and Rosenberg et al, Dig. Dis., Vol. 20, page 721(1975). Several controlled trials support the use of AZA in ulcerativecolitis, the most recent by Hawthorne et al in Brit. Med. J., Vol. 305,page 20 (1992). However, use of 6 MP and AZA has been limited byconcerns about their toxicities. Dose-related leukopenia is seen in 2-5%of patients treated long-term with 6 MP or AZA for IBD. See, forexample, Present et al, Am. Int. Med., Vol. 111, page 641 (1989); andConnell et al, Gut, Vol. 34, page 1081 (1993).

[0014] It is an object of the present invention to provide a novel anduseful therapy for IBD.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015]FIG. 1 sets forth the chemical formulae for various of thecompounds described herein.

[0016] FIGS. 2-8 depict the results of tests performed on rat colonsutilizing the methods and compositions of the present invention.

SUMMARY OF THE INVENTION

[0017] The above and other objects are realized by the presentinvention, one embodiment of which relates to a composition in unitdosage form for the inhibition, prevention or treatment of inflammatorybowel disease comprising an effective amount of a compound and apharmaceutically acceptable carrier therefor, the compound having theformula:

[0018] and the salts thereof with pharmaceutically acceptable acids andbases.

[0019] An additional embodiment of the invention concerns a novel methodfor the inhibition, prevention or treatment of inflammatory boweldisease comprising administering to a human or non-human mammal in needthereof an effective amount of a compound having the formula:

DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention is predicated on the discovery that IBD maybe successfully prevented or treated and its onset greatly inhibited bytreatment with one or more of the above-identified compounds. Moreover,some of these compounds have been shown to be virtually non-toxic, evenat relatively massive dosages. Furthermore, the compounds of theinvention have been found to be far superior to the conventionallyemployed 5-ASA for the treatment of IBD in animal models.

[0021] Several of the compounds employed in the compositions of thepresent invention, as well as methods for their preparation, aredescribed in U.S. patent application Ser. No. 08/624,289 filed Mar. 29,1996; and Ser. No. 09/144,103 filed Aug. 31, 1998, and U.S. Pat. Nos.5,493,053; 5,322,961; 5,364,965; 5,367,113 and 5,254,724, the entirecontents and disclosures of each of which are incorporated herein byreference.

[0022] The compounds of formula [B] may be prepared by esterifyingp-cresol with 3-chloropropionyl chloride; heating the product with aFriedel-Crafts catalyst to give the B-chloroketone. Diethylacetamidomalonate is C-alkylated with the chloroketone to yield anopen-chain intermediate which is cyclized, e.g., by refluxing withconcentrated HCl, to give the pyrrole carboxylic acid. The carboxylicacid group may then be esterified to give any desired ester.

[0023] More specifically,3,4,-dihydro-5-(2-hydroxy-5-methylphenyl)-2H-pyrrole-2-carboxylic acidmay be prepared as follows:

EXAMPLE

[0024] 4-Methylphenyl 3-Chloropropanoate (19). 3-Chloropropionylchloride (12.5 ml, 0.131 mol) was added for three minutes to a solutionof p-cresol (12.90 g, 0.119 mol) in pyridine (9.5 ml, 0.12 mol) andCH₂Cl₂ (53 ml) at 0° C. After stirring the reaction mixture for one dayat 0° C. to room temperature, solvent was removed by rotary evaporation.The concentrate was treated with brine (50 ml) and 0.5 M citric acid(150 ml) and extracted with EtOAc (3×100 ml). The organic extracts werewashed with 100 ml; 1 N HCl, H₂O, cold 0.1 N NaOH, H₂O and brine. Aftersolvent removal, the residue was purified by silica gel flash columnchromatography eluting with 7.5% EtOAc/hexane to give 12.90 g (55%) of19 as a colorless liquid: NMR δ 2.34 (s, 3H), 3.03 (t, 2H, J=7), 3.86(t, 2H, J=7), 6.95-7.01 (m, 2H), 7.17 (d, 2H, J=8).

[0025] 2-(3-Chloropropionyl)-4-methylphenol (20). AlCl₃ (38.9 g, 0.292mol) was added to 19 (12.89 g, 64.9 mmol); the exothermic reaction wascontrolled by brief cooling in ice water. The reaction mixture washeated at 90-95° C. with stirring under an N₂ balloon with periodicventing of the HCl for 69 minutes. The reaction flask was cooled to 0°C. and cold 0.5 N HCl (300 ml) was added, slowly at first. The aqueousphase was extracted with EtOAc (250 ml, 3×100 ml). The organic extractswere washed with H₂O (100 ml) and brine (100 ml). After solvent removal,the solid was chromatographed on a silica gel flash column eluting with26% CH₂Cl₂/pet ether yielding 10.21 g (79%) of 20 as a pale green solid:NMR δ 2.32 (s, 3H), 3.48 (t, 2H, J=7), 3.92 (t, 2H, J=7), 6.91 (d, 1H,J=8), 7.31 (dd, 1H, J=8, 2), 7.49 (s, 1H), 11.84 (s, 1H). Anal. calcd.for C₁₀H₁₁ClO₂: C 60.46, H 5.58. Found: C 60.72, H 5.63.

[0026] Diethyl acetamidomalonate (12.84 g, 59.11 mmol) was added tofreshly prepared 0.29 M NaOEt (225 ml) in EtOH at 0° C. The solutionresulting after brief sonication was transferred to an addition funneland added over six minutes to a suspension of 20 (10.68 g, 53.74 mmol)in EtOH (50 ml) at 0° C. After stirring the reaction mixture for 18hours at room temperature, solvent was removed in vacuo. Cold 0.25 N HCl(200 ml) was added and the aqueous phase was extracted with CHCl₃ (200ml, 2×100 ml). The organic layer was washed with H₂O (100 ml). Aftersolvent removal, the solid was purified by silica gel flash columnchromatography using 4% acetone/—CH₂Cl₂ to furnish 18.1 g (89%) ofdiethyl(acetylamino)[3-(2-hydroxy-5-methylphenyl)-3-oxopropyl]propanedioate (I)as a solid: NMR δ 1.26 (t, 6H, J=7), 2.04 (s, 3H), 2.30 (s, 3H), 2.78(t, 2H, J=7), 2.98 (t, 2H, J=7), 4.17-4.34 (m, 4H), 6.79 (s, 1H), 6.88(d, 1H, J=8), 7.25-7.30 (m, 1H), 7.47 (s, 1H), 11.97 (s, 1H). Anal.calcd. for C₁₉H₂₅NO₇: C 60.15, H 6.64, N 3.69. Found: C 60.23, H 6.73, N3.77.

[0027] Concentrated HCl (140 ml) was added to I and the reaction mixturewas heated at reflux under an N₂ balloon with periodic venting for 15hours. Solvent was removed under high vacuum, the residue was dissolvedin H₂O (120 ml) and evaporation was repeated. Distilled H₂O (120 ml) wasadded to the solid and solvent was removed by lyophilization to give12.96 g (quantitative) of3,4-dihydro-5-(2-hydroxy-5-methylphenyl)-2H-pyrrole-2-carboxylic acid asa green solid: NMR (D₂O) δ 2.30 (s, 3H), 2.33-2.46 (m, 1H), 2.67-2.82(m, 1H), 3.59-3.68 (m, 2H), 5.10 (dd, 1H, J=10, 6), 7.04 (d, 1H, J=8),7.52-7.58 (m, 1H), 7.59-7.62 (m, 1H). Anal. calcd. for C₁₂H₁₄ClNO₃: C56.37, H 5.52, N 5.48. Found: C 56.19, H 5.62, N 5.41.

[0028] Several of the compounds described above are characterized by theasymmetric carbon atom marked with an asterisk (*). The bondssurrounding these carbon atoms are arranged tetrahedrally and thesubstituents thus bonded to the asymmetric carbon atoms are in fixedpositions. The formula represents optical antipodes exhibiting eitherthe (S)- or (R)-conformation. Racemates can be split in a manner knownper se, for example, after conversion of the optical antipodes intodiastereoisomers, for example, by reaction with optically active acidsor bases.

[0029] A typical model of IBD in acetic acid-induced colitis in the rathas been described by Krawisz et al in Amer. J. Proc. Gastro. Col. Rec.Surg., Vol. 31, pages 11-18 (1980); and by Sharon et al inGastroenterology, Vol. 88, pages 55-63 (1985) and Vol. 86, pages 453-460(1984). Acetic acid-induced colitis is characterized by the movement ofinflammatory cells into the colon, with the number of such cells in themucosa being measured by the activity of myeloperoxidase, a markerenzyme for these cells. Positive desirable activity is indicated by areduction in the high levels of myeloperoxidase caused by acetic acid.

[0030] Typically, Sprague-Dawley rats from Charles River Laboratories,Portage, Mich. (either sex, weight approximately 250 g) are dosed withtest compounds and controls. Thereafter, the rats are given anintracolonic enema of acetic acid which produces a severe inflammatoryresponse in the colon of a healthy rat characterized by rectal bleeding,diarrhea, epithelial erosions and destructions of crypts and glandcells. Twenty-four hours later, the test and control animals aresacrificed and the distal ten centimeters of the colons are removed andopened longitudinally. The tissue lesions contained within the removed,opened section of the colons are scored.

[0031] After the systematic evaluation of the impact of various fastingtimes, use of vehicles, the time interval between pre-treatment andadministration of the acetic acid and altering the concentration ofacetic acid, the final protocol for the experiments is to fast the ratsfor 30 hours in hanging wire cages, anesthetize the animals with sodiumpentobarbital, administer the test drug 1 cc intrarectally (i.r.) eitheras a suspension or a solution in water, and to give the acetic acid(7.5% in water) 1 cc i.r. 30 minutes later. The rats are sacrificed 24hours later and the colons are removed and assessed for damage.

[0032] The compounds tested against the above-described model are setforth in FIG. 1.

[0033] Results:

[0034] DFO and DFT given i.r. at a dose of 650 μmol/kg were ineffective.However, when either the N-methylhydroxamate or the 2H-pyrrolecarboxylicacid were given i.r. at 650 μmol/kg (165 or 166 mg/kg, respectively) 30minutes before acetic acid, very little damage was noted in the colonsof any of the test animals. See FIGS. 2-8. Experiments with the lattercompound have been expanded, and very little damage has been noted inthe colons of any of the rats treated with this compound. When thecompound was evaluated head-to-head with 5-ASA or its commerciallyavailable formulation (Rowasa), the compound was found to be farsuperior even at a much lower dose (650 μmol/kg vs. 1742 μmol/kg). See,for example, FIGS. 7 and 8. In addition, preliminary acute toxicitystudies in mice have shown the 2H-pyrrolecarboxylic acid to be virtuallynon-toxic, with no deaths even when injected intraperitoneally (i.p.) atdoses up to 1 g/kg.

[0035] Thus, the results depicted in FIGS. 2-8 show that there isconsiderably less damage to the colons of rats treated with the2H-pyrrolecarboxylic acid than to the colons of control rats. In furtherreversal studies, lesions in the group given the 2H-pyrrolecarboxylicacid 30 minutes after 2.5% acetic acid were less severe and less activethan those in the control group. The lesions were apparently resolvingand with some lamina proprial fibrosis and considerable hyperplasia ofsubmucosal lymphoid tissue. A dose response study was performed withsevere lesions being prevented in a majority of rats at a dose of 162.5μmol/kg (41.5 mg/kg) at 1 cc i.r. This 2H-pyrrolecarboxylic acid is arelatively easy and inexpensive molecule to synthesize. In addition,although the drug binds iron remarkably well in a test tube, it has beenfound to be inactive as an iron chelator when given to rats orally orsubcutaneously (s.c.). This is a highly desirable property, as patientssuffering from IBD are already anemic due to disease-related blood loss.

[0036] It has been established, therefore, that the compounds used inthe method of the present invention can treat inflammatory boweldisease. The term “inflammatory bowel disease,” as used for purposes ofthe present invention, means any disorder of the digestive system whichis characterized by inflammation. Examples of such disorders includeCrohn's disease, mucous colitis, ulcerative colitis, pseudomembranousenterocolitis, non-specific colonic ulcers, collagenous colitis,cathartic colon, ulcerative proctitis, radiation enteritis and colitis,idiopathic diffuse ulcerative non-granulomatous enteritis, non-steroidalanti-inflammatory drug induced inflammations, celiac sprue and the like.

[0037] The method of the present invention comprises administering to amammal suffering from inflammatory bowel disease an effective amount ofone or more of the compounds of the invention. Administration may beaccomplished either therapeutically or prophylactically by means ofpharmaceutical compositions which are prepared by techniques well knownin the pharmaceutical sciences.

[0038] While the compounds of the invention are preferably administeredorally or intrarectally, they may also be administered by a variety ofother routes such as transdermally, subcutaneously, intranasally,intramuscularly and intravenously.

[0039] The present invention is also directed to pharmaceuticalcompositions which include at least one compound as described above inassociation with one or more pharmaceutically acceptable diluents,excipients or carriers therefor.

[0040] In making the pharmaceutical compositions of the presentinvention, one or more compounds will usually be mixed with, diluted byor enclosed within a carrier which may be in the form of a capsule,sachet, paper or other container. When the carrier serves as a diluent,it may be a solid, semi-solid or liquid material which acts as avehicle, excipient or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 60% by weight of active compound, soft and hard gelatincapsules, suppositories, sterile injectable solutions and sterilepackaged powders.

[0041] Some examples of suitable carriers, excipients and diluentsinclude lactose, dextrose, sucrose, sorbitol, mannitol, starches, gumacacia, calcium phosphate, alginates, tragacanth, gelatin, calciumsilicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose,water, syrup, methyl cellulose, methyl- and propyl-hydroxybenzoates,talc, magnesium stearate and mineral oil. The formulations canadditionally include lubricating agents, wetting agents, emulsifying andsuspending agents, preserving agents, sweetening agents or flavoringagents. The compositions of the invention may be formulated so as toprovide rapid, sustained or delayed release of the active ingredientafter administration to the patient by employing procedures well knownin the art.

[0042] The dose of the compound is that amount effective to preventoccurrence of the symptoms of the disease or to treat some symptoms ofthe disease from which the patient suffers. By “effective amount,”“therapeutic amount” or “effective dose” is meant that amount sufficientto elicit the desired pharmacological or therapeutic effects, thusresulting in effective prevention or treatment of the disease.Prevention of the disease is manifested by a prolonging or delaying ofthe onset of the symptoms of the disease. Treatment of the disease ismanifested by a decrease in the symptoms associated with the disease oran amelioration of the recurrence of the symptoms of the disease.

[0043] The effective dose may vary, depending upon factors such as thecondition of the patient, the severity of the symptoms of the diseaseand the manner in which the pharmaceutical composition is administered.

[0044] The compositions are formulated, preferably in a unit dosageform, such that each dosage contains from about 100 to about 12,000 mg,more usually about 250 to about 6,000 mg, of the active ingredient. Theterm “unit dosage form” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with one or moreof the above-described suitable pharmaceutical diluents, excipients orcarriers.

[0045] The compounds are effective over a wide dosage range in treatingTBD. Thus, as used herein, the term “effective amount” refers to adosage range of from about 1 to about 3,000 mg/kg of body weight perday. In the treatment of adult humans, the range of about 2 to about 500mg/kg, in single or divided doses, is preferred. However, it will beunderstood that the amount of compound actually administered will bedetermined by a physician in light of the relevant circumstances,including (1) the condition to be treated, (2) the choice of compound tobe administered, (3) the chosen route of administration, (4) the age,weight and response of the individual patient, and (5) the severity ofthe patient's symptoms. Therefore, the above dosage ranges are notintended to limit the scope of the invention in any way.

I claim:
 1. A composition in unit dosage form for the inhibition,prevention or treatment of inflammatory bowel disease comprising aneffective amount of a compound and a pharmaceutically acceptable carriertherefor, the compound having the formula:

wherein: Z is CH or N; R is H or acyl; R₁, R₂, R₃ and R₅ may be the sameor different and represent H, alkyl or hydrocarbyl arylalkyl having upto 14 carbon atoms; and R₄ is H, alkyl having 1-6 carbon atoms or OR. 2.A composition according to claim 1 wherein said compound has theformula:


3. A composition according to claim 2 wherein said compound is the(R)-enantiomer thereof.
 4. A composition according to claim 2 whereinsaid compound is the (S)-enantiomer thereof.
 5. A composition accordingto claim 1 wherein said compound has the formula:


6. A composition according to claim 5 wherein said compound is the(R)-enantiomer thereof.
 7. A composition according to claim 5 whereinsaid compound is the (S)-enantiomer thereof.
 8. A composition accordingto claim 1 wherein said effective amount is sufficient to provide adosage when administered to a human or non-human mammal in need thereofof from about 2 to about 500 mg/kg.
 9. A method for the inhibition,prevention or treatment of inflammatory bowel disease comprisingadministering to a human or non-human mammal in need thereof aneffective amount of a compound having the formula [A] or [B] of claim 1.10. The method of claim 9 wherein said compound is topicallyadministered to the colon of said mammal.
 11. The method of claim 10wherein said compound is administered by rectal enema or by means of anorally ingested unit dosage.
 12. The method of claim 11 wherein saidcompound is administered in an amount in the range of from about 2 toabout 500 mg/kg.
 13. A composition in unit dosage form adapted fortopical administration to the colon of a human or non-human mammal forthe inhibition, prevention or treatment of inflammatory bowel diseasecomprising an effective amount of desferrioxamine B, a homolog or analogthereof and a pharmaceutically acceptable carrier therefor, saiddesferrioxamine B, homolog or analog thereof having the formula:

wherein: each n may be the same or different and is an integer from1-10; each m may be the same or different and is an integer from 2-6; aand b are integers from 1-6; c is an integer from 0-10; R is a straightor branched chain alkyl having 1-14 carbon atoms or aryl; and R₁ and R₂are straight or branched chain alkyls having 1-10 carbon atoms.
 14. Acomposition according to claim 13 comprising desferrioxamine B.
 15. Acomposition according to claim 13 wherein said effective amount issufficient to provide a dosage when administered to a human or non-humanmammal in need thereof of from about 2 to about 500 mg/kg.
 16. A methodfor the inhibition, prevention or treatment of inflammatory boweldisease comprising topically administering to the colon of a human ornon-human mammal in need thereof an effective amount of a compoundhaving the formula [C], [D], [E] or [F] of claim
 13. 17. The method ofclaim 16 wherein-said compound is administered by rectal enema or bymeans of an orally ingested unit dosage.